La monografia sui PCB: PCB e melanoma - ATS Brescia · 2016-12-19 · Group 2A : Possibly carcinogenic to humans . Group 2B : Not classifiable as to carcinogenicity . Group 3 : Probably

La monografia sui PCB: PCB e melanoma

Béatrice Lauby-Secretan, PhD Section of the IARC Monographs

http://monographs.iarc.fr/

Outline

The IARC Monographs – Procedure – Evaluation

PCB and melanoma – Cohort studies – Case-control studies – Mechanistic data – Evaluation

How are evaluations conducted? Published guidelines & procedures •Participant selection

•Conflict of interest

•Data eligibility •Review of evidence

•Decision process for overall evaluations

•Public participation

http://monographs.iarc.fr/ENG/Preamble/index.php

IARC Secretariat

Coordinates all aspects of the

evaluation

Working Group Independent scientists

without conflict of interest

Review science and develop evaluations

Invited Specialists Scientists with relevant

knowledge but a competing interest

Representatives of governments and

health agencies

Observers Scientists with a

competing interest: observe but do not influence outcomes

Who does the evaluation? Attend meetings but do not write reviews or contribute

to evaluations

What evidence is considered?

Overall Evaluation

Publicly available scientific data • Peer-reviewed articles • Government reports

• Available in enough detail for critical

review

Cancer in humans

Cancer in Experimental

animals Mechanistic and other relevant

data

Exposure Data

What are the IARC classifications? Carcinogenic to humans Group 1 Probably carcinogenic to humans Group 2A Possibly carcinogenic to humans Group 2B Not classifiable as to carcinogenicity Group 3 Probably not carcinogenic to humans Group 4

• IARC classifications refer to the strength of scientific evidence (the level of certainty that the agent causes cancer)

• They DO NOT reflect the level of carcinogenic risk

How are the data evaluated? Cancer in humans

Evidence suggesting lack of carcinogenicity

Sufficient evidence

Limited evidence

Inadequate evidence

Causal relationship has been established Chance, bias, and confounding could be ruled out with

reasonable confidence

Causal interpretation is credible Chance, bias, or confounding could not be ruled out

Studies permit no conclusion about a causal association

Adequate studies covering the full range of exposure are consistent in not showing a positive association at any level of exposure

Cancer in Experimental

animals

Mechanistic and other relevant data

How are overall evaluations determined?

Sufficient Limited Inadequate

EVIDENCE IN EXPERIMENTAL ANIMALS

Carcinogenic to humans (Group 1)

EVID

ENC

E IN

HU

MA

NS Sufficient

Limited

Inadequate

Examples Group 1 • Asbestos • Tobacco smoking

How are overall evaluations determined?

Sufficient Limited Inadequate

EVIDENCE IN EXPERIMENTAL ANIMALS

EVID

ENC

E IN

HU

MA

NS

Probably carcinogenic

(Group 2A)

Sufficient

Limited

Inadequate

Examples Group 2A • DDT • Tetrachloroethylene

How are overall evaluations determined?

Sufficient Limited Inadequate

EVIDENCE IN EXPERIMENTAL ANIMALS

EVID

ENC

E IN

HU

MA

NS

Possibly carcinogenic (Group 2B)

Possibly carcinogenic (Group 2B)

Sufficient

Limited

Inadequate Examples Group 2B • Chloroform • Styrene

How are overall evaluations determined?

Sufficient Limited Inadequate

EVIDENCE IN EXPERIMENTAL ANIMALS

EVID

ENC

E IN

HU

MA

NS

Not classifiable (Group 3)

Sufficient

Limited

Inadequate

How are overall evaluations determined? Mechanistic modifications

Sufficient Limited Inadequate

EVIDENCE IN EXPERIMENTAL ANIMALS

Group 1 (carcinogenic to humans)

EVID

ENC

E IN

HU

MA

NS

Group 2A (probably carcinogenic)

Group 3 (not classifiable)

Group 2B (possibly carcinogenic) (exceptionally, Group 2A)

Group 2B (possibly carcinogenic)

Sufficient

Limited

Inadequate

Strong evidence in exposed humans

The IARC Monographs process

Selection of intervention

Selection of experts

Writing

assignments

Monograph

meeting

Scientific editing

English editing

Final read

Publication (print, on-line, e-pub)

M-12 M-10 M-8 M M+2 M+6 M+8 M+12

Outline

The IARC Monographs – Procedure – Evaluation

PCB and melanoma – Cohort studies – Case-control studies – Mechanistic data – Evaluation

Skin toxicity of PCBs • Studies on exposure of capacitor workers to PCBs

suggested that these compounds are well absorbed by skin contact

• Chloracne and other dermal alterations are well known effects of long-term exposure to PCBs and related compounds

• Interference of PCBs with the metabolism of vitamin A in the skin, resulting in disturbances of the epithelial tissues of the pilo-sebaceous duct (Coenraads et al., 1994).

Studies assessing the link between exposure to PCBs and cancer (≤ 2012)

Cohorts • Occupational cohort studies (n=13)

• Cohorts of accidental exposure (Yusho, Yucheng, with 4 follow-up each)

• Cohorts of high dietary exposure (fishermen’s wives) (n=5)

• General population cohorts (n=15)

Case-controls • Non-Hodgkin lymphoma (n=17)

• Breast (n=32)

• Other sites (prostate, testis, lung, pancreas, biliary tract, colorectum,

endometrium, skin, uveal melanoma, children leukemia)

1.a Cohort studies in capacitor-manufacturing workers

Ruder et al. (2006), Indiana, USA, 1957–1998

3569 Melanoma

Cumulative exposure Sex, age, race, calendar period Lowest tertile 5 SMR, 3.7 (1.2–8.7)

Middle tertile 2 SMR, 1.5 (0.2–5.4)

Highest tertile 9 SMR, 2.4 (1.1–4.6) P for trend = 0.72

Prince et al. (2006b), Massachusetts & New York, USA, 1939–1998

14 458

Melanoma

Cumulative exposure Sex, age, race, calendar period < 150 unit-yr 1 Results for 0-yr lag 150 to < 620 unit-yr 2 RR, 0.3 (0.1–1.3) > 620 unit-yr 6 RR, 0.7 (0.2–1.9) P for trend = 0.83 Workers employed ≥ 90 days

All workers 19 SMR, 1.26 (0.76–1.97) Male 14 SMR, 1.66 (0.91–2.79) Female 5 SMR, 0.75 (0.24–1.75) New York 14 SMR, 1.79 (0.98–3.00) Massachusetts 5 SMR, 0.69 (0.22–1.61)

Kimbrough et al. (2003), New York, USA, 1946–1998

7075 Skin, including melanoma

Hourly workers (employed ≥ 90 days as non-salaried workers)

9 [SMR, 1.2 (0.6–2.4)] Sex, age, race, calendar period

Salaried workers 6 [SMR, 2.1 (0.8–4.7)] Same plant as Prince et al. (2006b)

1.b Cohort study in transformer -manufacturing and -repair

workers Yassi et al. (1994, 2003), Manitoba, Canada, 1946–1995; 1950–1995 (mortality); 1969–1995 (incidence)

2222 men

Melanoma

Duration of employment:

> 6 mo 8 SMR, 1.8 (0.2–6.4) 13% excluded from original mortality study because of missing identifiers. Total of deaths until 1995: 261 in cohort, 104 in subcohort, 31 in transformer-assembly department

> 1 mo 10 SIR, 2.2 (1.1–4.0)

1.c Cohort studies in electric-power and telecommunications

workers De Guire et al. (1988, 1992), Montreal, Canada, 1976–1983

9590

> 6 mo employment. Exposed to polyvinyl chloride, soldering fumes, and PCBs

Men 3 SMR, 3.0 (0.6–8.8)

Women 1 SMR, 4.8 (0.1–27)

Men, < 20 yr latency 2 SMR, 9.4 (1.1–34)

Men, > 20 yr latency 1 SMR, 1.3 (0.0–7.1)

Women, < 20 yr latency 1 SMR, 12.1 (0.0–67)

Tynes et al. (1994), Norway, 1920–1991; 1953–1991

5088 men

Worked ³ 1 yr at any of eight hydroelectric-power companies

Employment > 1 yr 19 SIR, 1.1 (0.7–1.8)

Ever exposed to PCBs 9 SIR, 1.8 [0.8–3.4] Incidence of

other cancers not analysed in association with PCB exposure

Ever exposed to PCBs, 0–15 µT-yr 0

Ever exposed to PCBs, > 15 µT-yr 9 SIR, 2.7 [1.2–5.2]

1.c Cohort studies in electric-power and telecommunications workers

(contnd) Loomis et al. (1997), California, North Carolina, Pennsylvania, Tennessee, Virginia, USA, 1950–1988

138 905 men

Potential PCB exposure: Age, calendar time, race, social class, active work status

0 to < 5 yr 25 RR, 1.3 (0.6–2.6) 5 to < 10 yr 9 RR, 1.1 (0.5–2.7) 10 to < 20 yr 11 RR, 1.4 (0.6–3.3) ³ 20 yr 8 RR, 1.6 (0.6–4.2) Cumulative PCB exposure (h), 0-yr lag:

> 0–2000 73 RR, 1.2 (0.6–2.5) > 2000–10 000 12 RR, 1.7 (0.7–7.1) > 10 000 3 RR, 1.9 (0.5–7.1) Cumulative PCB exposure (h), 20-yr lag:

> 0 to 2000 42 RR, 1.3 (0.8–2.2) > 2000–10 000 8 RR, 2.6 (1.1–6.0) > 10 000 1 RR, 4.8 (1.5–15) RR per 2000 h cumulative PCB exposure (continuous variable):

0-yr lag - RR, 1.02 (0.99–1.05) 20-yr lag - RR, 1.05 (1.01–1.09)

• Robinson et al., 1999 – Proportional mortality study among 31’000 electrical

workers employed in the construction industry – Excess mortality: PMR, 1.23 (1.02-1.47) – Exposure to PCB could not be confirmed (also

exposure to other agents) • Bahn et al., 1976

– 2 cases of melanoma among 31 workers in research and development and refinery industry

– SIR, 50.0 (95% CI, 5.6 – 217)

1.d Cohort studies with other industrial exposures to PCBs

1.e Cohort studies with high dietary intake of PCBs

Reference, location, follow-up period

Total No. of subjects

Exposure assessment

Organ site Exposure categories

Exposed cases

Relative risk (95% CI)

Covariates Comments

Mikoczy & Rylander (2009) Sweden 1968–2002 (east coast) 1965–2002 (west coast)

2042 (east coast) and 6674 (west coast) fishermen's wives

Dietary intake of fatty fish from Baltic Sea (east coast)

Comparison with national rates

SIR (95% CI) Age Possible coexposure to PCDDs and PCDFs West Coast Melanoma 38 1.03 (0.73–1.41)

Skin 60 1.43 (1.09–1.84) East coast Melanoma 8 0.76 (0.33–1.49)

Skin 9 0.95 (0.43–1.80) Helmfrid et al. (2012) Gusum, Sweden 1960–2003

Residents in contaminated area (number not given)

Consumption of foods from contaminated local river

Overall, compared with national death rates

SIR (95% CI) Age, time period; Possible coexposure to metals because of industrial activities

Men Melanoma 15 1.56 (0.87–3.94) Women Melanoma 11 1.22 (0.60–2.19)

Exposure categories

Exposed cases

Relative risk (95% CI)

Covariates Comments

Age, sex, education, skin reaction to repeated sun exposure, and total recreational sun exposure

Total PCBs 98.01–148.71 11 1.36 (0.45–4.09) 148.72–213.44 12 1.27 (0.39–4.12) > 213.44 29 6.02 (2.00–18.17) P for trend < 0.001 DL-PCBs 9.37–15.10 8 0.31 (0.10–0.98) 15.11–22.57 16 1.16 (0.41–3.26) > 22.57 25 2.84 (1.01–7.97) P for trend = 0.003 NDL-PCBs 86.68–133.66 12 2.05 (0.66–6.39) 133.67–192.39 11 1.19 (0.36–3.90) > 192.39 30 7.02 (2.30–21.43) P for trend < 0.001 PCB-118 > 4.90–8.16 13 0.89 (0.34–2.34) > 8.16–13.32 14 1.13 (0.40–3.23) > 13.32–46.19 23 3.04 (1.05–8.74) P for trend = 0.012 PCB-138 > 12.79–20.76 19 1.89 (0.68–5.28) > 20.76–30.65 8 1.30 (0.37–4.56) > 30.65–104.49 28 4.91 (1.69–14.32)

2. Population-based case-control study

Gallagher et al. (2011) British Columbia, Canada 2000–2004 80 Cases 310 controls Exposure assessment: Lipid-adjusted concentrations of 14 PCBs (units NR): PCB 28, 52, 99, 101, 105, 118, 128, 138, 153, 156, 170, 180, 183, and 187.

Exposure categories Exposed cases

Relative risk (95% CI)

Covariates Comments

PCB-153 > 27.75–42.07 14 2.01 (0.70–5.77) > 42.07–60.43 12 1.35 (0.43–4.25) > 60.43–735.90 27 4.86 (1.68–14.08) P for trend = 0.002 PCB-156 > 4.09–6.07 13 1.04 (0.36–2.97) > 6.07–8.65 13 1.48 (0.49–4.45) > 8.65–113.32 29 4.22 (1.51–11.78) P for trend = 0.001 PCB-170 > 7.97–12.16 13 1.50 (0.53–4.29) > 12.16–18.51 13 1.10 (0.32–3.77) > 18.51–901.52 29 4.60 (1.60–13.22) P for trend = 0.001 PCB-180 > 25.20–38.16 12 1.46 (0.49–4.37) > 38.16–59.40 14 1.55 (0.44–5.43) > 59.40–3786.60 30 5.89 (1.87–18.50) P for trend = 0.001 PCB-183 > 1.87–84.86 54 4.27 (1.71–10.68) PCB-187 > 6.64–10.45 11 2.54 (0.75–8.58) > 10.45–16.10 15 2.56 (0.76–8.62) > 16.10–833.15 30 11.47 (3.32–39.68) P for trend < 0.001

3. Evaluation • Elevated number of cancers observed consistently in

studies of: – workers (cohorts in North America and Europe)

• Manufacture of capacitors & transformers (four studies) • electric power and telecommunication workers (three studies) • equipment maintenance (two studies)

– the general population, with measures of PCB levels in blood (case-control study in Canada)

• In the largest study, the risk increased with the dose • Increase of uveal melanoma (cancer of the eye) in

workers exposed to PCB oils There is sufficient evidence in humans for an association

between exposure to PCBs and malignant melanoma

4. Relevant biological effects

PCB mix Cytotoxicity / Cell proliferation Immunotoxicity

Genetic and related effects

Epigenetic effects

Aryl hydrocarbon receptor-mediated

effects

Metabolic activation

Endocrine effects (hormones)

Organ toxicity (liver, skin)

Inflammatory response

Structure-activity relationship

The IARC Monographs Section

The IARC Monographs and Handbooks are supported by grants from: U.S. National Cancer Institute (since 1982) European Commission, DG Employment, Social Affairs and Inclusion (since 1986) U.S. National Institute of Environmental Health Sciences (since 1992) Institut National du Cancer (INCa), France U.S. Center for Disease Control (CDC) American Cancer Society

Molto grazie per l’invito